Indole derivatives in the treatment of skeletal muscle fatigability

ABSTRACT

SKELETAL MUSCLE FATIGABILITY IS TREATED BY ADMINISTRATION OF A COMPOSITION CONTAINING A SKELETAL MUSCLE STIMULANT WHICH IS A DERIVATIVE OF INDOLE-3-ACETIC ACID OR OF INDOLE-3YLMETHYLTETRAZOLE.

United States Patent US. Cl. 424-269 9 Claims ABSTRACT OF THE DISCLOSURE Skeletal muscle fatigability is treated by administration of a composition containing a skeletal muscle stimulant which is a derivative of indole-3-acetic acid or of indole-3- ylmethyltetrazole.

This is a division of application Ser. No. 92,299, filed Nov. 23, 1970, now US. Patent No. 3,689,657.

This invention is concerned with a novel method for producing muscle stimulation in animals which comprises the administration of derivatives of indole.

The agents found useful in this novel method of treatment can be illustrated by the following structural formula, (I)

wherein R represents (1) COZ, wherein Z represents (a) hydroxyl,

(b) lower alkoxy of from 1 to about 8 carbon atoms, either straight or branch chained and either unsubstituted or substituted with (i) di(lower alkyl) aminomethyl, wherein the lower alkyl groups have from 1 to about 3 carbon atoms, such as methyl, ethyl and propyl,

(ii) hydroxy,

(iii) phenyl, either unsubstituted or substituted with nitro, halo such as chloro, bromo or fiuoro, or lower alkyl of l to about 3 carbon atoms,

(iv) lower alkoxy of from 1 to about 3 carbon atoms,

(c) phenoxy, either unsubstituted or substituted with nitro, halo such as fluoro, chloro or bromo, or lower alkyl of from 1 to about 3 carbon atoms,

(2) tetrazol-S-yl. R represents (1) hydrogen, (2) lower alkyl of 1 to about 3 carbons, (3) lower alkenyl of from 3 to about 5 carbon atoms,

such as allyl, butenyl and the like; R represents (1) lower alkyl of 1 to about 8 carbon atoms, either straight or branch chained and either unsubstituted or substituted with (a) lower alkoxy of 1 to about 3 carbons,

(b) lower alkylthio of 1 to about 3 carbons,

(2) lower alkylcarbonyl, wherein the lower alkyl group has from 1 to about 5 carbon atoms;

R represents (1) hydrogen,

(2) lower alkyl of 1 to about 3 carbon atoms, either unsubstituted or substituted with halo or lower alkoxy of 1 to about 3 carbon atoms,

(3) nitro,

(4) halo such as chloro, bromo or fluoro.

The active agents of the method of this invention have been found in standard laboratory animals to produce myotonic symptoms consisting of temporary rigid exten sion of the legs when the animal is disturbed. The overt appearance is readily distinguishable from convulsions caused by central stimulation. This stimulation of striated muscle is useful in the treatment of disease entities characterized by progressive fatigability of the muscles such as myasthenia gravis.

Present day therapy for myasthenia gravis generally involves a class of agents termed acetylcholinesterase inhibitors and/or skeletal muscle facilitators. These substances often exhibit side effects such as extreme salivatio-n, involuntary defacation and urination, sweating, lacrimation, bradycardia and hypotension. They have a relatively low therapeutic index and are not always effective. The compounds of the novel method of this invention on the other hand operate through a mechanism of action difierent from that of the acetylcholinesterase inhibitors and fail to produce any of the adverse side-eifects described above in experimental animals, and have a much higher therapeutic index. They have further been shown to facilitate the activity of acetylcholinesterase inhibitors and therefore may also be used in combination with them to reduce their toxicity.

Treatment with the active agents of this invention can be orally in the form of powders, granules, wafers, tablets, capsules or pills, or by injection intravenously, or intraperitoneally in suspension or in solution. Where Z is hydroxyl they can be administered as a pharmaceutically acceptable salt, such as an alkali metal salt, preferably the potassium or sodium salt. The dose is from 1 to about 50 mgs./kg./day either singly or on a multidose regimen depending on the severity of the disorder and the discretion of the physician.

These active muscle stimulant products wherein R is a carboxyl group can be prepared by the prior art multistep process outlined below:

3 A detailed description of the synthesis of Compound VII wherein R is butyl and R is S-methyl, is included in Example I below.

The preparation of ester derivatives of Compound VII are performed by standard chemical syntheses well known 4 (63.3%) of 3 dimethylaminomethyl)-2-butyl-5-methylindol'e, m.p. 108.5-110.5 C.

Step D: Preparation of 2-butyl-3-(cyanomethyl)-5- methylindole ous), 7.15 ml. of dimethylamine (37% aqueous), 32.5 ml. of glacial acetic acid, and 32.5 ml. of dioxane at a temperature maintained below C. After the addition is complete, the reaction mixture is allowed to warm to room temperature .over a period of 18 hours. Itv is diluted with 300 ml. water and filtered to remove a small amount of gummy .by-product. The filtrate is chilled in an icebath and made'ba sic" (pH 101l) with lON KOH. The precipitated product is filtered, washed with Water and dried. Recrystallization from n-hexane gives 5.0 g.

in the art, and a detailed procedure is included in the ex- 5 A solution of 3.42 g. (0.014 mole) of 3-dimethylamino- -amples below methyl)-5-methyl-2-butylindole dissolved in 60 ml. dry

The preparation f 3 compound h i R i g t L ether is added dropwise with stirring to an ice-cooled soluis described in Example 5 tion of 19.5 ml. of iodomethane and stirred for 6 hours 10 at 0 C. The precipitate is filtered, washed with ether and E A P 1 dried to yield 4.7 g. (87%) 0f the methiodide salt of 3- d 1 Acid (dimethylaminornethyl)-5-methyl-2-butylindole. 2 Butyl 5 M ethy m 0 e f 1 Without further purification, the methiodide is added to p AI Pffipal'atlon of N'gzA'dlmethylphenyl) a solution of 8.93 g. potassium cyanide in 68.3 ml. of Pentananfllde water and maintained at 80 C. with stirring for 2 hours. A Solution of 22] (0188 mole) f pentanoyl h1 After cooling, the reaction mixture is extracted with ether, ride in 100 ml. tetrahydrofuran is added over minutes thefithel Solution is Washed with Water dried over to a stirred, ice-cooled solution of 121.2 g. (1 mole) 1- 1165mm Sulfate and evaporated to a risldllal YellOW amino-2,4-dimethylbenzene. After standing for several 0f y y y y hours at room tempefature the solvent is {emoved by 20 Step B: Preparation of 2-butyl-5-methylindole-3-acetic distillation in vacuo. The residue is taken up in ether and acid extracted with 12N HCl to remove excess l-amino-2,4- dimethylbenzene. After washing to neutrality and drying The mmle (0-0128 solutlon over magnesium sulfate, the ether solution is concentrated of 1153 (0205 mole) potasswm hydroxlde m 39 to yield 25.1 g. of N-(2,4-dimethylphenyl)pentanamide, 25 of water and 64 eihanol and for i w m'p 1144150 C. under a blanket of nitrogen. The reaction mixture is diluted with 500 ml. water, acidified to pH 2 with concen- P BI Preparation of z'butylr5'methyhndole trated hydrochloric acid and extracted with ether. The To a Stirred Solution of 205 (01 mole) f ether extract is washed with water, dried over magnesium dimethylphenyl)pentanamide in m1 diethylaniline sulfate and evaporated to a crystalline residue, 3.1 g. under nitrogen, is added in portions 20 (0526 mole) (90%). Recrystallization from petroleum ether yields 2- of sodamide. The mixture is heated slowly to 220 C. and b1tyl'5me thYl1nd0le'3'aceuc and, -P- maintained at this temperature for 5 hours. The reaction Employmg the Procedure of Examine 1 but $ub$t1tut1ng mixture is cooled to about 50 C., and the excess sodamfor lhe l?entanoyl ,chlorlfie and l'ammo'zii'dlmethylben' ide Carefully desomposcd by the addition of 300 mL of zene utilized therein equivalent quantities of an acid chlowater- The organic phase is extracted into 300 ml. ether nde of formula Rzcocl and a benzene denvatlve of and washed with portions of cold 4N HCl and water, structure The ether solution is dried and concentrated to 20.2 g. of residual solid. Recrystallization from petroleum ether i gives 2-butyl-5-methylindole, mp. 73.5-75.5 c. 40 QI NH Step C: Preparation of 3-(dimethylaminomethyl)-2- butyl-S-methylindole A solution of 6.087 g. (0.0325 mole) of 2-butyl-5- there are produced the substituted indoleacetic acids demethylindole in 32.5 ml. dioxane is added dropwise to a picted in Table I.

TABLE I CH3 8 1 011200011 R 0 R o 001 -Z R F NH Steps R2 Ex. R1 R2 3 6 13 5-C H3 -CH2CH(OH3)2 5-CH3 n-CaH7 6-CH3 n-(QJaEr- 205 9- 2 5 CH -CH=CH n-O 3H 1 a-CHZ I1C3H1- 5 CH3 11-C3H7- H n-CiH1 5-01 n-CaH1 5-F -(CH2)3OCII3 5-CH3 H2CF3 5CF3 (CII2)3SCH3 5-CII3 I1 3H7 5'CH2OCH3 stirred solution of 3.25 ml. of formaldehyde (25% aque- EXAMPLE 16 Methyl S-methyl-Z-propylindole-3-acetate The solution is concentrated to dryness and the residue is fractionally distilled. The distillate (b.p. 132150/0.3 mm. Hg) crystallizes spontaneously and is recrystallized from petroleum ether to yield 1.75 g. of methyl S-methyl- 2-propylindole-3-acetate, mp. 75 .5-78" C.

EXAMPLE 17 Octyl 5-methyl-2-propylindoIe-B-acetate 5-methyl-2-propylindole-3-acetic acid (3.45 g., 15 mmole) is stirred into 80 mls. of n-octyl alcohol and through this mixture is bubbled dry hydrogen chloride for 3 minutes. The mixture is stirred at ambient temperature for 18 hours. Excess solvent is removed under high vacuum at a temperature below 130 C. The oily residue is dissolved in ether, washed with water, dried over magnesium sulfate, treated with decolorizing charcoal, filtered and concentrated to dryness. The residue is recrystallized from a methanol-water mixture to give octyl 5- methyl-2-propyl-indole-3-acetate, mp. 35-37 C.

Employing the procedure of Example 17 but substituting for the octanol and the S-methyl-2-propylindole-3- acetic acid utilized therein equivalent amounts of an alcohol of formula ZH and a 1-R -2-R -5(or 6)-R -indole-3-acetic acid described in Table II, there are produced the Z 1-R -2-R -5(or 6)-R -indole-3-acetates, also described in Table II.

extract on concentration and cooling gives 2-propyl-5- nitroindole-3-acetic acid (4.32 g.). Evaporation of the chloroform mother liquors gives a powdery residue which on chromatography on a silica gel column, gives an additional 9 g. of the nitro compound, mp. 195-200 C. (36.2%).

EXAMPLE 34 2-propionylindole-3-acetic acid EXAMPLE 5- 5 -methyl-2-propylindole-3-ylmethyl tetrazole To a solution of 1.8 g. (0.0085 mole) of 3-cyanomethyl- 5-methyl-2-propylindole in 20 ml. methyl Cellosolve is added 1.1 g. (0.017 mole) powdered sodium amide and TABLE II ornooon crnooz ZH R R EX. R R R Z M.P. C.)

18"-.- H. n-CZH'I H OCH3 Liquid 19 H n-C3H7 5-011 0 74. 5-76. 5

20- H IA-CQH'] H 'OCHICH(OH)CH Liquid 21-.." H a 'l 5-CH3 --0C2H5 Liquid 22 H n-C H 5-CH Liquid 23 H n-C3H1 H Same as above 62. 5-64. 0 H n-C3H1 5-CH3 -O (CH2)2N(CH3)2 5 69. 5 n-C3H 5-CH3 OCH d H Il-C3H1 5-CH3 OC2H4OCH3 H CH OCH 5-011 27.. 2)3 a a (NEED N02 CH CH=CH n-C H 5-CH 28 z z a 1 a OCH2 f Cl --C2H n-C H 5-F H CH CF 5-CF H CH SCH G'CH 31 2): a a 0 f E C1 32 OH:; Il-CaH' 5-CH2OCH3 O f F EXAMPLE 33 0.72 g. (0.017 mole) powdered lithium chloride and the 5-nitro-2-propylindole-3-acetic acid A solution of sodium nitrate (11.76 g.) in concentrated sulfuric acid (300 ml.) is added dropwise with stirring to a solution of 2-propylindol-2-acetic acid (30 g.) in concentrated sulfuric acid maintained at 5 C. in an icebath. The solution is stirred for /2 hour and poured into ice-water. The yellow precipitate is filtered and washed with water. The solid is dissolved in ethyl acetate, dried, and the solvent evaporated and the gummy residue is extracted several times with chloroform. The chloroform propylindole-3-yl-methyl)tetrazole, m.p. 183-184 C.

Employing the methodof Example 35 but substituting for the 3 cyanornethyl S-methyl-Z-propylindole used therein, equivalent amounts of the 3-cyan0methyl-5-R -2- R lR -indoles described in Table III, there are produced the 5 (5-R -2-R -l-R -indol-3ylmethyl)tetrazoles also described in Table III.

The active agents of the method of this invention were found in standard laboratory animals to produce myotonic symptoms consisting of temporary rigid extension of the legs when the animal is disturbed.

The compounds were initially tested for skeletal muscle stimulant properties at doses of 32 mg./kg. intra-peritoneally (i.p.). Effective doses (ED were then determined for active compounds by that route, and subsequently by intravenous (i.v.) and oral (p.o.) administration.

Although toxicities were not accurately determined in all cases, no lethality was observed during the ED determinations.

The procedure used for i.p., i.v. and p.o. administrations was as follows:

Groups of male albino mice (Swiss strain, Canadian Breeding Laboratories), weighing 18-22 grams were employed. Compounds were suspended in 1% Methocel (methyl cellulose, 400 cps, 65 Hg) with the aid of an homogenizer and administered, i.v., i.p. or p.o. in a volume of 0.2 ml./ 20 g. of body weight.

The results obtained following the above procedure upon the administration of the skeletal muscle stimulant agents of this invention indicate that the ED by intravenous, intraperitoneal, and oral administration are in the ranges O.4-7l, 0.7-30, 0.5-14 mgJkg. respectively.

It is to be noted that in so far as the active agents of this invention are concerned, no gross toxic symptoms were observed in any of the animals at the dose levels employed.

The amount of muscle stimultant agent to be employed in the method of this invention will depend upon the age, condition, weight and other factors relevant to the animal to be treated and necessarily needs to be individualized by the physician or veteriarian for each patient. A suitable unit dosage form for oral administration is described in the following example:

EXAMPLE 36 Capsule containing 25 mgs. of active ingredient Ingredient: mgs./ capsule 5-methyl-2-propylindole-3-acetic acid 25 Corn starch U.SP. l

Lactose U.S.P. 130

25 g. of -methyl-2-propylindole-3-acetic acid is intimately blended with g. corn starch U.S.P. The mixture is filled into No. 4 gelatin capsules using conventional methods known in the art to produce oral dosage units each containing 25 mg. 5-methyl-2-propylindole-3-acetic acid.

EXAMPLE 37 lnjectable preparation containing 10 mg. of active ingredient I The sodium salt of 5 methyl-2-propylindole-3-acetic acid is dissolved in pyrogen free water at a concentration 8 of 10 ing/ml. and the resulting solution is dispensed into 1 cc. pharmaceutical vials.

The soluble salts can be formed from any pharmaceutically acceptable materials such as sodium, potassium, ammonia, amines, and the like. The active ingredients can also be administered in aqueous suspension as the procaine salt. In addition the active ingredients can be administered in aqueous suspension as the free acids or as the esters described herein.

What is claimed is:

1. A method of treatment of skeletal muscle fatigability which comprises the administration to an affected animal of an effective amount of a skeletal muscle stimulant having the structural formula i 5V1 V:

3. A composition for the treatment of skeletal muscle fatigability which comprises an eifective amount of a skeletal muscle stimulant having the structural formula wherein R is tetrazol-S-yl; R is a member selected from the group consisting of (1) hydrogen, (2) lower alkyl, and '(3) lower alkenyl; R is a member selected from the group consisting of (1) lower alkyl, (2) lower alkoxy-lower alkyl, (3) lower alkylthio-lower alkyl, 4) w,w,w-trifiuorolower alkyl, and (5) lower alkylcarbonyl; R is a member selected from the group consisting of (1) hydrogen, (2) lower alkyl, (3) halo-lower alkyl, (4) lower alkoxy-lower alkyl,

9 10 (5) nitro, and (6 halo; and a pharmaceutically acceptable carrier.

4. The composition of Claim 3 wherein the carrier is I'O' N N orally pharmaceutically acceptable. 5

5. The composition of Claim 3 wherein the carrier is l intraveneously pharmaceutically acceptable.

6. The composition of Claim 3 wherein the carrier is Whfifell1 R2 and R3 are as defined m lm 4- intraperitoneally acceptable. 9. The composition of Claim 4 wherein the muscle 7. The composition of Claim 3, wherein the muscle 10 stlmulant has Structural formula stimulant has structural formula N*-NH C CH5- I OH; CHr- N=N N CHgCHgCH3 H CHzCHzCH;

No references cited.

8. The composition of Claim 4 wherein the muscle sti l t h structural form la STANLEY J. FRIEDMAN, Primary Examiner 

